β-cell function in new-onset type 1 diabetes and immunomodulation with a heat-shock protein peptide (DiaPep277): a randomised, double-blind, phase II trial

Background Type 1 diabetes results from autoimmune destruction of insulin-producing pancreatic β cells. The 60 kDa heat-shock protein (hsp60) is one of the known target self antigens. An immunomodulatory peptide from hsp60, p277, arrested β-cell destruction and maintained insulin production in newly diabetic NOD mice. We did a randomised, double-blind, phase II study of peptide treatment in patients with newly diagnosed (<6 months) type 1 diabetes. Methods 35 patients with type 1 diabetes and basal C-peptide concentrations above 0·1 nmol/L were assigned subcutaneous injections of 1 mg p277 and 40 mg mannitol in vegetable oil (DiaPep277; n=18) at entry, 1 month, and 6 months, or three placebo injections (mannitol in vehicle; placebo; n=17). The primary endpoint was glucagon-stimulated C-peptide production. Secondary endpoints were metabolic control and T-cell autoimmunity to hsp60 and to p277 (assayed by cytokine secretion). 31 patients completed 10 months of follow-up and were included in the intention-to-treat analysis. Findings At 10 months, mean C-peptide concentrations had fallen in the placebo group (n=16) but were maintained in the DiaPep277 group (n=15; 0·26 [SD 0·11] vs 0·93 [0·35] nmol/L; p=0·039). Need for exogenous insulin was higher in the placebo than in the DiaPep277 group (0·67 [0·33] vs 0·43 [0·17] U/kg; p=0·042). Haemoglobin A1c concentrations were low (around 7%) in both groups. T-cell reactivity to hsp60 and p277 in the DiaPep277 group showed an enhanced T-helper-2 cytokine phenotype. No adverse effects were noted. Interpretation Although this study was small, treatment of newly diagnosed type 1 diabetes with DiaPep277 seems to preserve endogenous insulin production, perhaps through induction of a shift from T-helper-1 to T-helper-2 cytokines produced by the autoimmune T cells.